The invention herein is directed to the cyclization of a methionine analog to a lactam using new reaction reagents and conditions. The invention herein is further directed to the enantioselective synthesis of ethyl 3-[[[[1-[4-(aminoiminomethyl)phenyl]-2-oxo-3(S)-pyrrolidinyl]amino]carbony l]amino]propionate acetate and related .beta.-alanine analogs. Such compounds are useful as antithrombotic agents.
More specifically the invention herein is directed to the conversion of a methionine analog such as ##STR3## (Z=H, --CN, --CONH.sub.2 or --CO.sub.2 Me) to a lactam such as ##STR4## using reagent and reaction conditions which are beneficial in comparison to previously disclosed methodology for achieving such a conversion.
Friedinger et al., J. Org. Chem., 47, (104-109), 1982 disclose general methods for the synthesis of lactam-constrained dipeptide analogs using three different paths from protected chiral .alpha.-amino acids to lactams. Included within this disclosure is a method for cyclizing methionine analogs to lactams via an alkylative cyclization involving a two step procedure using highly volatile and toxic methyl iodide and highly reactive sodium hydride as reagents.
It would be desirable to provide a process for conversion of a methionine analog to a lactam via conditions which do not employ volatile, toxic or highly reactive reagents and which produces a lactam having high enantiomeric purity.